The present invention relates to plant-derived chemotherapeutic compounds. More particularly, the invention is directed to deoxygenated taxol compounds prepared from a natural product which is isolated from Taxus canadensis, as well as novel analogs of taxol prepared therefrom.
Taxol, a member of the taxane family of terpenes, is of interest as a chemotherapeutic agent against a broad range of cancers. Derived primarily from the Pacific yew Taxus brevifolia, taxol has been shown to be active against advanced breast and ovarian cancers in clinical trials, and has exhibited promising activity against a number of other tumor types in preliminary investigations. A summary of the current state of taxol research, development and clinical testing may be found in Rotherberg, Curr. Opin. Invest. Drugs, 1(12):1269-1277 (1993); a review of synthetic efforts in the taxol field is provided by D. G. I. Kingston in Prog. Chem. Org. Nat. Prod., 61:1-206 (1993).
Although taxol, which possesses the structural formula ##STR2## has shown considerable therapeutic potential, its scarcity in nature and the need for more potent cytostatic agents have led researchers to pursue alternative sources as well as analogs of the compound. Some efforts have been made to produce taxol in tissue and cell culture. Total chemical synthesis of the compound and its related analogs has been attempted but has not yet been achieved. The chemical conversion of naturally occurring taxol precursors such as baccatin III and cephalomannine to taxol itself or its analogs has been reported; however, additional routes for the production of potentially active taxanes are still needed.
One line of inquiry has focused on a more abundant taxane precuror, 13-acetyl-9-dihydrobaccatin III, which can be obtained from the widely distributed Canadian yew Taxus canadensis as described in published international application No. PCT/US93/03532, published on Oct. 28, 1993 as publication No. WO 93/21173 and incorporated herein by reference. This 9-dihydro modication makes possible the preparation of a new series of taxol analogs.
Modifications of the C-7 and C-10 positions of the baccatin moiety, including 7-deoxy, 10-desacetoxy and 7,10-dideoxytaxol derivatives, have also been described. 7-Deoxybaccatin or 7-deoxytaxol derivatives have been described in the international (PCT) application publication No. WO 93/02064, published Feb. 4, 1993 and J. Org. Chem. 58:3798-3799 (1993). 10-Desacetoxytaxol derivatives have been described in the international (PCT) application publication No. WO 93/06093, published Apr. 1, 1993; U.S. Pat. No. 5,248,796, published Sep. 28, 1993; European Patent Application EP 558959, published Sep. 8, 1993; J. Org. Chem. 58:2927-2928 (1993); and Tetrahedron Lett. 34(31):4921-24 (1993). 7,10-Dideoxytaxol derivatives have been described in J. Org. Chem. 58:5028-5029 (1993) and Tetrahedron Lett. 34(43):6845-6848 (1993).
Certain patents and patent applications also purport to generically disclose 9-deoxotaxanes, namely, U.S. Pat. Nos. 4,876,399, 5,015,744 and 5,175,315 and international (PCT) application publication No. WO 93/20036. While these disclosures refer generically to 9-deoxo compounds, they contain no teaching as to how to prepare these compounds and contain no specific examples, prophetic or actual, of 9-deoxo taxanes. Consequently, these disclosures provide no more than a motivation to attempt the preparation of such compounds.
In fact, the ability to synthesize 9-deoxygenated compounds having potentially superior biological or pharmacologic properties may offer significant advantages to the chemist and pharmacologist. It is therefore an object of the present invention to provide such compounds and the means for their preparation.